chr10-99533243-C-A

Position:

• chr10-99533243-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_145285.3(NKX2-3):​c.112C>A​(p.His38Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: NKX2-3 NM_145285.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

Genes affected

NKX2-3 (HGNC:7836): (NK2 homeobox 3) This gene encodes a homeodomain-containing transcription factor. The encoded protein is a member of the NKX family of homeodomain transcription factors. Studies of similar proteins in mouse and rat have indicated a potential role in cellular differentiation.[provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.126264).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKX2-3	NM_145285.3	c.112C>A	p.His38Asn	missense_variant	1/2	ENST00000344586.9	NP_660328.2
NKX2-3	XM_011539370.2	c.112C>A	p.His38Asn	missense_variant	1/2		XP_011537672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKX2-3	ENST00000344586.9	c.112C>A	p.His38Asn	missense_variant	1/2	2	NM_145285.3	ENSP00000342828.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459982 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 725910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2024

The c.112C>A (p.H38N) alteration is located in exon 1 (coding exon 1) of the NKX2-3 gene. This alteration results from a C to A substitution at nucleotide position 112, causing the histidine (H) at amino acid position 38 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.90	N;.
REVEL	Benign	0.23
Sift	Benign	0.58	T;.
Sift4G	Benign	0.45	T;T
Polyphen		0.0010	B;.
Vest4		0.26
MutPred		0.22		Gain of relative solvent accessibility (P = 0.1066);Gain of relative solvent accessibility (P = 0.1066);
MVP		0.79
ClinPred		0.12	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2033929554; hg19: chr10-101293000;